Non-missense variants ofKCNH2show better outcomes in type 2 long QT syndrome

Abstract

Aims More than one-third of type 2 long QT syndrome (LQT2) patients carry KCNH2 non-missense variants that can result in haploinsufficiency (HI), leading to mechanistic loss-of-function. However, their clinical phenotypes have not been fully investigated. The remaining two-thirds of patients harbour missense variants, and past studies uncovered that most of these variants cause trafficking deficiency, resulting in different functional changes: either HI or dominant-negative (DN) effects. In this study, we examined the impact of altered molecular mechanisms on clinical outcomes in LQT2 patients. Methods and results We included 429 LQT2 patients (234 probands) carrying a rare KCNH2 variant from our patient cohort undergoing genetic testing. Non-missense variants showed shorter corrected QT (QTc) and less arrhythmic events (AEs) than missense variants. We found that 40% of missense variants in this study were previously reported as HI or DN. Non-missense and HI-groups had similar phenotypes, while both exhibited shorter QTc and less AEs than the DN-group. Based on previous work, we predicted the functional change of the unreported variants—whether they cause HI or DN via altered functional domains—and stratified them as predicted HI (pHI)- or pDN-group. The pHI-group including non-missense variants exhibited milder phenotypes compared to the pDN-group. Multivariable Cox model showed that the functional change was an independent risk of AEs (P = 0.005). Conclusion Stratification based on molecular biological studies enables us to better predict clinical outcomes in the patients with LQT2.

From gene-specific to function-specific risk stratification in long QT syndrome Type 2: implications for clinical management

“…A plausible alterative explanation could be a different representation of missense variants causing HI or DN effect in the two cohorts. Indeed, in the study by Aizawa et al , 78% (186/239) of patients with missense variants were in the DN or pDN group, 7 while in the study by Shimizu et al , with all the limitations of extrapolating numbers from published data, the percentage could go from a minimum of 30% (260/860) considering only patients with missense variants in the pore region to a maximum of 35% (304/860) including also patients with missense variants in transmembrane S1–S4 that contains the voltage sensor domain. 8 In any case, there is an overrepresentation of missense variants in the DN group in the study by Aizawa et al compared to the study by Shimizu et al ( P < 0.0001) that could justify the different result obtained comparing missense vs. non-missense variant independently on their functional consequences.…”

“…The study by Aizawa et al , published on the current issue of the journal, took a further step forward in the understanding on how genetic basis can influence the arrhythmic risk in the Type 2 variant of LQTS. 7 Indeed, all the studies so far published 4 ,5, 8 correlated clinical severity with the location of the mutation in the protein or with the type of disease-causing genetic variant, but this is the first study that attempted to correlate the functional consequences of the variants with arrhythmic risk. The authors studied a population of 429 LQT2 patients, followed in two Japanese referral centres, carrying 178 unique KCNH2 variants, 102 missense and 76 non-missense, the latter including non-sense, frameshift, or splicing variants.…”

“…The authors studied a population of 429 LQT2 patients, followed in two Japanese referral centres, carrying 178 unique KCNH2 variants, 102 missense and 76 non-missense, the latter including non-sense, frameshift, or splicing variants. 7 They divided all these variants into two major functional subgroups, those leading to haploinsufficiency (HI) and those causing a dominant-negative (DN) effect. For those not familiar with these terms, haploinsufficiency occurs when only a single copy of the gene is functional.…”

“… 9 Missense variants ( n = 102) were classified into HI or DN group according to previously published functional data in 41 of them and according to predictions based on protein localization in the remaining 61. 7 Specifically, the authors classified missense variants in the pore region and in the voltage sensor domain as variants with a presumed dominant-negative effect (pDN) and those in all other regions as presumed HI (pHI). The authors started comparing patients with non-missense variants, missense variants with established HI, and missense variants with established DN effect.…”

“…Finally, multivariate analysis confirmed DN status as an independent risk factor for cardiac events in the population under investigation. 7 …”